Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide

Emanuela Colombo, Marco Di Dario, Eleonora Capitolo, Linda Chaabane, Jia Newcombe, Gianvito Martino, Cinthia Farina

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

Objective: Although astrocytes participate in glial scar formation and tissue repair, dysregulation of the NFκB pathway and of nitric oxide (NO) production in these glia cells contributes to neuroinflammation and neurodegeneration. Here we investigated the role of the crosstalk between sphingosine-1-phosphate (S1P) and cytokine signaling cascades in astrocyte activation and inflammation-mediated neurodegeneration, and addressed the effects of fingolimod on astrocyte-neuron interaction and NO synthesis in vivo. Methods: Immunohistochemistry, immunofluorescence, and confocal microscopy were used to detect S1P receptors, interleukin (IL) 1R, IL17RA, and nitrosative stress in multiple sclerosis (MS) plaques, experimental autoimmune encephalomyelitis (EAE) spinal cord, and the spinal cord of fingolimod-treated EAE mice. An in vitro model was established to study the effects of S1P, IL1, and IL17 stimulation on NFkB translocation and NO production in astrocytes, on spinal neuron survival, and on astrocyte-neuron interaction. Furthermore, fingolimod efficacy in blocking astrocyte-mediated neurodegeneration was evaluated. Results: We found coordinated upregulation of IL1R, IL17RA, S1P1, and S1P3 together with nitrosative markers in astrocytes within MS and EAE lesions. In vitro studies revealed that S1P, IL17, and IL1 induced NFκB translocation and NO production in astrocytes, and astrocyte conditioned media triggered neuronal death. Importantly, fingolimod blocked the 2 activation events evoked in astrocytes by either S1P or inflammatory cytokines, resulting in inhibition of astrocyte-mediated neurodegeneration. Finally, therapeutic administration of fingolimod to EAE mice hampered astrocyte activation and NO production. Interpretation: A neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key astrocyte activation steps.

Original languageEnglish
Pages (from-to)325-337
Number of pages13
JournalAnnals of Neurology
Volume76
Issue number3
DOIs
Publication statusPublished - Sep 1 2014

Fingerprint

Astrocytes
Nitric Oxide
Autoimmune Experimental Encephalomyelitis
Neurons
Neuroglia
Neuroprotection
Fingolimod Hydrochloride
Multiple Sclerosis
Spinal Cord
Lysosphingolipid Receptors
Cytokines
Interleukins
Neuroprotective Agents
Conditioned Culture Medium
Fluorescence Microscopy
Confocal Microscopy
Cicatrix
Up-Regulation
Immunohistochemistry
Inflammation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Medicine(all)

Cite this

Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. / Colombo, Emanuela; Di Dario, Marco; Capitolo, Eleonora; Chaabane, Linda; Newcombe, Jia; Martino, Gianvito; Farina, Cinthia.

In: Annals of Neurology, Vol. 76, No. 3, 01.09.2014, p. 325-337.

Research output: Contribution to journalArticle

Colombo, E, Di Dario, M, Capitolo, E, Chaabane, L, Newcombe, J, Martino, G & Farina, C 2014, 'Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide', Annals of Neurology, vol. 76, no. 3, pp. 325-337. https://doi.org/10.1002/ana.24217
Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G et al. Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Annals of Neurology. 2014 Sep 1;76(3):325-337. https://doi.org/10.1002/ana.24217
Colombo, Emanuela ; Di Dario, Marco ; Capitolo, Eleonora ; Chaabane, Linda ; Newcombe, Jia ; Martino, Gianvito ; Farina, Cinthia. / Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. In: Annals of Neurology. 2014 ; Vol. 76, No. 3. pp. 325-337.
@article{72a30310615f4520b76b7675a58bf77a,
title = "Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide",
abstract = "Objective: Although astrocytes participate in glial scar formation and tissue repair, dysregulation of the NFκB pathway and of nitric oxide (NO) production in these glia cells contributes to neuroinflammation and neurodegeneration. Here we investigated the role of the crosstalk between sphingosine-1-phosphate (S1P) and cytokine signaling cascades in astrocyte activation and inflammation-mediated neurodegeneration, and addressed the effects of fingolimod on astrocyte-neuron interaction and NO synthesis in vivo. Methods: Immunohistochemistry, immunofluorescence, and confocal microscopy were used to detect S1P receptors, interleukin (IL) 1R, IL17RA, and nitrosative stress in multiple sclerosis (MS) plaques, experimental autoimmune encephalomyelitis (EAE) spinal cord, and the spinal cord of fingolimod-treated EAE mice. An in vitro model was established to study the effects of S1P, IL1, and IL17 stimulation on NFkB translocation and NO production in astrocytes, on spinal neuron survival, and on astrocyte-neuron interaction. Furthermore, fingolimod efficacy in blocking astrocyte-mediated neurodegeneration was evaluated. Results: We found coordinated upregulation of IL1R, IL17RA, S1P1, and S1P3 together with nitrosative markers in astrocytes within MS and EAE lesions. In vitro studies revealed that S1P, IL17, and IL1 induced NFκB translocation and NO production in astrocytes, and astrocyte conditioned media triggered neuronal death. Importantly, fingolimod blocked the 2 activation events evoked in astrocytes by either S1P or inflammatory cytokines, resulting in inhibition of astrocyte-mediated neurodegeneration. Finally, therapeutic administration of fingolimod to EAE mice hampered astrocyte activation and NO production. Interpretation: A neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key astrocyte activation steps.",
author = "Emanuela Colombo and {Di Dario}, Marco and Eleonora Capitolo and Linda Chaabane and Jia Newcombe and Gianvito Martino and Cinthia Farina",
year = "2014",
month = "9",
day = "1",
doi = "10.1002/ana.24217",
language = "English",
volume = "76",
pages = "325--337",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "3",

}

TY - JOUR

T1 - Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide

AU - Colombo, Emanuela

AU - Di Dario, Marco

AU - Capitolo, Eleonora

AU - Chaabane, Linda

AU - Newcombe, Jia

AU - Martino, Gianvito

AU - Farina, Cinthia

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Objective: Although astrocytes participate in glial scar formation and tissue repair, dysregulation of the NFκB pathway and of nitric oxide (NO) production in these glia cells contributes to neuroinflammation and neurodegeneration. Here we investigated the role of the crosstalk between sphingosine-1-phosphate (S1P) and cytokine signaling cascades in astrocyte activation and inflammation-mediated neurodegeneration, and addressed the effects of fingolimod on astrocyte-neuron interaction and NO synthesis in vivo. Methods: Immunohistochemistry, immunofluorescence, and confocal microscopy were used to detect S1P receptors, interleukin (IL) 1R, IL17RA, and nitrosative stress in multiple sclerosis (MS) plaques, experimental autoimmune encephalomyelitis (EAE) spinal cord, and the spinal cord of fingolimod-treated EAE mice. An in vitro model was established to study the effects of S1P, IL1, and IL17 stimulation on NFkB translocation and NO production in astrocytes, on spinal neuron survival, and on astrocyte-neuron interaction. Furthermore, fingolimod efficacy in blocking astrocyte-mediated neurodegeneration was evaluated. Results: We found coordinated upregulation of IL1R, IL17RA, S1P1, and S1P3 together with nitrosative markers in astrocytes within MS and EAE lesions. In vitro studies revealed that S1P, IL17, and IL1 induced NFκB translocation and NO production in astrocytes, and astrocyte conditioned media triggered neuronal death. Importantly, fingolimod blocked the 2 activation events evoked in astrocytes by either S1P or inflammatory cytokines, resulting in inhibition of astrocyte-mediated neurodegeneration. Finally, therapeutic administration of fingolimod to EAE mice hampered astrocyte activation and NO production. Interpretation: A neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key astrocyte activation steps.

AB - Objective: Although astrocytes participate in glial scar formation and tissue repair, dysregulation of the NFκB pathway and of nitric oxide (NO) production in these glia cells contributes to neuroinflammation and neurodegeneration. Here we investigated the role of the crosstalk between sphingosine-1-phosphate (S1P) and cytokine signaling cascades in astrocyte activation and inflammation-mediated neurodegeneration, and addressed the effects of fingolimod on astrocyte-neuron interaction and NO synthesis in vivo. Methods: Immunohistochemistry, immunofluorescence, and confocal microscopy were used to detect S1P receptors, interleukin (IL) 1R, IL17RA, and nitrosative stress in multiple sclerosis (MS) plaques, experimental autoimmune encephalomyelitis (EAE) spinal cord, and the spinal cord of fingolimod-treated EAE mice. An in vitro model was established to study the effects of S1P, IL1, and IL17 stimulation on NFkB translocation and NO production in astrocytes, on spinal neuron survival, and on astrocyte-neuron interaction. Furthermore, fingolimod efficacy in blocking astrocyte-mediated neurodegeneration was evaluated. Results: We found coordinated upregulation of IL1R, IL17RA, S1P1, and S1P3 together with nitrosative markers in astrocytes within MS and EAE lesions. In vitro studies revealed that S1P, IL17, and IL1 induced NFκB translocation and NO production in astrocytes, and astrocyte conditioned media triggered neuronal death. Importantly, fingolimod blocked the 2 activation events evoked in astrocytes by either S1P or inflammatory cytokines, resulting in inhibition of astrocyte-mediated neurodegeneration. Finally, therapeutic administration of fingolimod to EAE mice hampered astrocyte activation and NO production. Interpretation: A neuroprotective effect of fingolimod in vivo may result from its inhibitory action on key astrocyte activation steps.

UR - http://www.scopus.com/inward/record.url?scp=84907873464&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907873464&partnerID=8YFLogxK

U2 - 10.1002/ana.24217

DO - 10.1002/ana.24217

M3 - Article

C2 - 25043204

AN - SCOPUS:84907873464

VL - 76

SP - 325

EP - 337

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 3

ER -